近日，美国纪念斯隆-凯特琳癌症中心Wungki Park团队报道了Setidegrasib治疗晚期非小细胞肺癌和胰腺癌的疗效与安全性。这一研究成果于2026年3月25日发表在《新英格兰医学杂志》上。

KRAS p.G12D变异见于5%的非小细胞肺癌（NSCLC）患者，同时也是胰腺导管腺癌中最常见的置换变异，发生于40%的患者中，但目前尚无针对该变异的靶向疗法获准用于临床。Setidegrasib（ASP3082）是首个靶向KRAS G12D的蛋白降解剂。

研究组开展了这项1期研究，旨在评估setidegrasib在既往接受过治疗、携带KRAS p.G12D变异的晚期实体瘤患者中的安全性、药代动力学、药效学和抗肿瘤活性。主要目标是评估安全性特征（以剂量限制性毒性作用和不良事件为终点指标），并确定2期推荐剂量。Setidegrasib采用静脉给药，每周一次，剂量范围为10～800 mg。

共有203例患者入组。在最终被选为2期推荐剂量的600 mg剂量组中，共76例患者接受了setidegrasib治疗，所有患者在治疗期间均出现不良事件，其中42%发生3级或更高级别事件。治疗相关不良事件发生率为93%；最常见的是短暂性输液相关反应（80%）和恶心（30%）。有2例患者因不良事件终止治疗。在接受600 mg剂量的45例NSCLC患者中，36%（95%置信区间[CI]，22～51）达到部分缓解，中位无进展生存期为8.3个月（95% CI，4.1～无法估计），估计的12个月总生存率为59%（95% CI，40～74）。在接受600 mg剂量作为二线或三线治疗的21例转移性胰腺导管腺癌患者中（其中67%接受setidegrasib作为三线治疗），24%（95% CI，8～47）达到缓解，中位无进展生存期为3.0个月（95% CI，1.4～6.9），中位总生存期为10.3个月（95% CI，4.2～13.0）。

研究结果表明，在既往接受过治疗的晚期KRAS p.G12D突变型NSCLC或胰腺导管腺癌患者中，setidegrasib表现出抗肿瘤活性，且因不良事件导致的治疗终止发生率较低。

附：英文原文

Title: Setidegrasib in Advanced Non–Small-Cell Lung Cancer and Pancreatic Cancer

Author: Wungki Park, Anup Kasi, Alexander I. Spira, Luis Paz-Ares Rodríguez, Benjamin O. Herzberg, Meredith S. Pelster, Anthony W. Tolcher, Yasutoshi Kuboki, Shigehisa Kitano, Hirokazu Shoji, Judy S. Wang, Jordan D. Berlin, Antoine Hollebecque, Patricia LoRusso, Christos Fountzilas, Philippe A. Cassier, Tomohiro Nishina, Daisuke Sakai, Chiaki Inagaki, Daniel Morgensztern, Makoto Ueno, Minkyu Jung, Sang-We Kim, Pasi A. Jnne, Antoine Italiano, Benot You, T Macarulla, Hisaki Fujii, Aditya Shetty, Ying Lu, Daniel Cui, Shilpa Kadam, Stanley C. Gill, Junko Toyoshima, Takeshi Saito, Jonathan W. Goldman

Issue&Volume: 2026-03-25

Abstract:

Background

The KRAS p.G12D variant occurs in 5% of patients with non–small-cell lung cancer (NSCLC) and is the most common substitution variant in pancreatic ductal adenocarcinoma, occurring in 40% of patients, but no targeted therapies directed against this variant are currently approved for clinical use. Setidegrasib (ASP3082) is a first-in-class KRAS G12D–targeted protein degrader.

Methods

We conducted this phase 1 study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of setidegrasib in patients with previously treated advanced solid tumors harboring KRAS p.G12D variants. The primary objectives were to evaluate the safety profile, as indicated by dose-limiting toxic effects and adverse events (the primary end points), and to determine the phase 2 dose. Setidegrasib was administered intravenously once weekly at doses of 10 to 800 mg.

Results

Overall, 203 patients were enrolled. Among the 76 patients who received setidegrasib at a dose of 600 mg, which was ultimately selected as the phase 2 dose, adverse events occurred during treatment in all the patients, with events of grade 3 or higher in 42%. Treatment-related adverse events occurred in 93% of the patients; the most common were transient infusion-related reactions (in 80%) and nausea (in 30%). Adverse events led to discontinuation in 2 patients. Among the 45 patients with NSCLC who received the 600-mg dose, 36% (95% confidence interval [CI], 22 to 51) had a partial response, the median progression-free survival was 8.3 months (95% CI, 4.1 to could not be estimated), and the estimated 12-month overall survival was 59% (95% CI, 40 to 74). Among the 21 patients with metastatic pancreatic ductal adenocarcinoma who received the 600-mg dose as second- or third-line treatment (of whom 67% received setidegrasib as third-line treatment), 24% (95% CI, 8 to 47) had a response, the median progression-free survival was 3.0 months (95% CI, 1.4 to 6.9), and the median overall survival was 10.3 months (95% CI, 4.2 to 13.0).

Conclusions

Setidegrasib was associated with antitumor activity and a low incidence of treatment discontinuation due to adverse events in patients with previously treated advanced KRAS p.G12D–mutated NSCLC or pancreatic ductal adenocarcinoma.

DOI: NJ202603250000001

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2600752